Dna Intercalation And Its Consequences

Many anticancer drugs in clinical use (e.g. anthracyclines, mitoxantrone, dactinomy-cin) interact with DNA through intercalation, which can be defined as the process by which compounds containing planar aromatic or heteroaromatic ring systems are inserted between adjacent base pairs perpendicularly to the axis of the helix and without disturbing the overall stacking pattern due to Watson-Crick hydrogen bonding. Since many typical intercalating agents contain three or four fused rings that absorb light in the UV-visible region of the electromagnetic spectrum, they are usually known as chromophores. Besides the chromophore, other substitu-ents in the intercalator molecule may highly influence the binding mechanism, the geometry of the ligand-DNA complex, and the sequence selectivity, if any.

The intercalation process1 starts with the transfer of the intercalating molecule from an aqueous environment to the hydrophobic space between two adjacent DNA base pairs. This process is thermodynamically favoured because of the positive entropy contribution associated to disruption of the organized shell of water molecules around the ligand (hydrophobic effect). In order to accommodate the ligand, DNA must undergo a conformational change involving an increase in the vertical separation between the base pairs to create a cavity for the incoming chromophore. The double helix is thereby partially unwound,2 which leads to distortions of the sugar-phosphate backbone and changes in the twist angle between successive base pairs (Fig. 7.1). Once the drug has been sandwiched

FIGURE 7.1 Deformation of DNA by an intercalating agent.

between the DNA base pairs, the stability of the complex is optimized by a number of non-covalent interactions, including van der Waals and p-stacking interactions,3 reduction of coulombic repulsion between the DNA phosphate groups associated with the increased distance between the bases because of helix unwinding, ionic interactions between positively charged groups of the ligand and DNA phosphate groups, and hydrogen bonding. Generally speaking, cationic species are more efficient DNA intercalators because they interact better with the negatively charged DNA sugar-phosphate backbone in the initial stages and also because intercalation releases counterions associated to phosphate group, such as Na+, leading to the so-called polyelectrolyte effect. This is a very important driving force for intercalation, since it diminishes repulsive interactions between the closely spaced charged counterions. In fact, most intercalating agents are either positively charged or contain basic groups that can be protonated under physiological conditions.

DNA intercalators are less sequence selective than minor groove binding agents, and, in contrast with them, show a preference for G-C regions. This selectivity is mainly due to complementary hydrophobic or electrostatic interactions, which are due to substituents attached to the chromophore within the major or minor grooves. DNA intercalation is also governed by the nearest-neighbour exclusion principle, which states that both neighbouring sites on each site of the intercalation remain empty, that is, they bind, at most, between alternate base pairs.4 This is an example of a negative cooperative effect, whereby binding to one site induces a conformational change that hampers binding to the adjacent base pair.

Intercalation of a drug molecule into DNA is only the first step in a series of events that eventually lead to its biological effects.5 Structural changes induced in DNA by intercalation lead to interference with recognition and function of DNA-associated proteins such as polymerases, transcription factors, DNA repair systems, and, specially, topoisomerases. The role of these enzymes in the design of antitumor drugs will be discussed in Sections 4 and 5.

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